Clearance of IgM sensitized RBC is entirely dependent on cell bound C3b. C3d coated cells do not get cleared from the circulation if IgM is the antibody responsible for their attachment. There are a limited number of sites for C3 binding when the C3 is activiated by cold agglutinin antibodies, and these sites differ for cold agglutinins and isoagglutinins. Cells with these sites occupied by C3d, the nonhemolytic fragment of C3, are less susceptible to lysis than normal cells. Rh antibodies were shown to require the classical complement pathway for optimal clearance; the fragment responsible for clearance of the cells was shown to be C3d. Thus, C3d cooperates with IgG antibody but not with IgM to produce clearance. Initial studies using the techniques developed in this program in examining other diseases have been completed and immunospecific defect in the clearance of particles from the circulation has been shown in patients with primary biliary cirrhosis.